Adenovirus-mediated targeted expression of toxic genes to adrenocorticotropin-producing pituitary tumors using the proopiomelanocortin promoter

Eun Jig Lee, Fred Martinson, Tom Kotlar, Bayar Thimmapaya, J. Larry Jameson

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Management of Cushing's disease remains challenging, despite advances in its diagnosis and treatment. Here, we describe a strategy for targeting the expression of toxic genes to ACTH-producing tumor cells using adenoviral vectors. The POMC promoter was used to express either a marker gene (β-galactosidase) or a toxic gene [herpes simplex virus thymidine kinase (TK)]. In ACTH-producing AtT20 cells, infection with recombinant adenoviruses containing the POMC promoter (AdPOMCGal; AdPOMCTK) led to high-level gene expression. Stereotactic injection of AdPOMCGal into the rat pituitary resulted in localized expression of the β-galactosidase transgene in corticotrope cells. Cytotoxicity studies were performed using the TK-containing vectors and treatment with ganciclovir. AdPOMCTK caused greater than 95% cytotoxicity of AtT20 cells at a viral dose (multiplicity of infection, 5 plaque-forming units/cell) that induced minimal toxicity using control viruses. No cellular toxicity was seen using a nonpituitary cell line (T47D breast tumor cells). ATT20 cells transplanted into nude mice induced features of Cushing's syndrome and were used as an in vivo model of ACTH-producing tumors. Injection of the AdPOMCTK virus caused significant regression of the transplanted ATT20 tumors. These studies suggest that the POMC promoter may provide a useful gene therapy strategy for the adjunctive treatment of pituitary tumors causing ACTH-dependent Cushing's syndrome.

Original languageEnglish
Pages (from-to)3400-3409
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume86
Issue number7
DOIs
Publication statusPublished - 2001 Aug 2

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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